Polymorphisms of many genes controlling metabolism of xenobiotic compounds and DNA repair processes are associated with susceptibility to cancer as well as other chronic diseases. We need studies that are more holistic in design and provide insights into the net effect on health of having specific genotypes. We propose a population-based cohort study to examine the broad impact of genetic variation in candidate genes and their interaction with environmental exposures on cancer incidence and survival specifically, and health and aging more generally. Participants (N=8395) of two blood and data specimen banks (CLUE I (1974) and CLUE II (1989)) comprise the study cohort (Odyssey Cohort). The cohort has been followed prospectively for 24 years and information on environmental factors such as smoking, education and housing are available as far back as 1963. DNA will be extracted from buffy coat specimens obtained from participants in 1989 and stored at - 70 C. We will investigate polymorphisms in genes coding for enzymes that:1) metabolize nutrients and hormones (MTHFR, VDR, CYP17, CYP1B1, COMT, CYP3A4 ); 2) metabolize carcinogens (ADH, GSTM1, GSTT1, GSTP1, NAT1 and NAT2, NOS, CYP1A1, CYP1B1, EH); and 3) control DNA repair processes (XRCC1, XRCC3, XPD). In this cohort, power is greater than 90 percent to detect a relative risk of 2 for main effects of genotypes on mortality and cancer incidence and at least 80 percent to detect gene-environment and gene-gene interactions of two-fold for the major cancer sites (such as breast, prostate and colorectal) and 3- to 5-fold for less common cancers such as endometrial and bladder cancer. As additional polymorphisms in candidate genes with potential relevance to the major health outcomes are identified we will be able to investigate their impact on health and survival, providing a valuable resource.